In Vitro Activities and Spectrum of the Novel Fluoroquinolone Lascufloxacin (KRP-AM1977)

Abstract

Lascufloxacin exhibited a broad spectrum of activity against various clinical isolates. Furthermore, lascufloxacin showed the most potent activity against Gram-positive bacteria among the quinolones tested and incomplete cross-resistance against existing quinolone-resistant strains. Enzymatic analysis indicated that lascufloxacin had potent inhibitory activity against both wild-type and mutated target enzymes. These results suggest that lascufloxacin may be useful in treating infections caused by various pathogens, including quinolone-resistant strains.KEYWORDS antimicrobial activity, antimicrobial agents, quinolones R ecently, the emergence of strains resistant to commercially available antibacterial drugs, including ␤-lactams, macrolides, tetracyclines, and aminoglycosides, has become a clinical problem around the world. Quinolones are also widely used for treatment of various infectious diseases, and the development of quinolone resistance in various bacteria has become a clinical concern. For example, a large proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolates showed resistance to quinolones (1, 2). For Streptococcus pneumoniae, a major causative organism of respiratory tract infections, the acquisition of resistance to quinolones has been reported in various areas of the world, including Southeast Asia (3). Therefore, the development of morepotent agents against resistant Gram-positive bacteria is required in preparation for the emergence of resistant strains.Lascufloxacin is a novel fluoroquinolone antibacterial agent newly developed in Japan (Fig. 1). This study was performed to determine the antibacterial activities of lascufloxacin against various clinical isolates. In addition, the activities of lascufloxacin against sequentially selected quinolone-resistant S. aureus, S. pneumoniae, and Escherichia coli were evaluated, and the inhibitory activities of lascufloxacin against target enzymes of wild-type and quinolone-resistant S. aureus were determined. Enterococcus faecalis and methicillin-susceptible S. aureus (MSSA), were limited to one isolate per patient; in some cases, two different bacterial strains, i.e., E. faecalis and MSSA, were isolated from one patient. Clinical strains of S. aureus MS5935, MS5952, MR5867, and MR6009 and their stepwise quinolone-resistant mutant strains were described previously (5). The quinolone-resistant S. pneumoniae isolates selected from strain IID553 were described previously (6). The quinolone-resistant E. coli GF4-3, CP4-1, and SP4-1 isolates were selected from K-12 strain KL-16 with gatifloxacin, ciprofloxacin,

In Vitro Activity of Lascufloxacin against Streptococcus pneumoniae with Mutations in the Quinolone Resistance-Determining Regions

“…Altogether, the stable activity of lascufloxacin against first-and second-step mutants of S. pneumoniae was thought to be due to the dual target properties and the inhibition of the mutated enzymes. A recent study indicated that lascufloxacin showed strong activity against S. pneumoniae, including fluoroquinolone-resistant strains, and an enzymatic analysis indicated that lascufloxacin showed potent inhibitory activities against DNA gyrase and topoisomerase IV with mutations in Staphylococcus aureus as well as against those without mutations (15). This report was consistent with our proposal regarding the activity of lascufloxacin.…”

In Vitro Mechanistic Study of the Distribution of Lascufloxacin into Epithelial Lining Fluid

“…Lascufloxacin and the other quinolones have high bioavailability and long plasma half-lives (bioavailability and half-life of lascufloxacin, 96% and 16.1 h; levofloxacin, 99% and 6.9 h; garenoxacin, 92% and 9.8 to 14.2 h; and grepafloxacin, 72% and 11.1 h, respectively) (4,32,33). Although the clinical dose and AUC in free plasma (fAUC) of lascufloxacin were lower than those of the existing quinolones (dosage and fAUC of lascufloxacin, 75 mg and 2.65 g · h/ml; levofloxacin, 500 mg and 33.1 g · h/ml; garenoxacin, 400 mg and 15.0 g · h/ml; and grepafloxacin, 400 mg and 6.35 g · h/ml) (lascufloxacin [in-house data of Kyorin Pharmaceutical Co., Ltd.]) (33), a Ͼ90% clinical efficacy rate was achieved in patients with respiratory tract infections (6).…”

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…Lascufloxacin, an 8-methoxyquinolone from Kyorin, is in phase III and shows improved activity for RTIpathogens.Itexertssome activity against MRSA, but with only limited application because of cross-resistance. [338,339] Finafloxacin, an 8-cyanofluoroquinolone from Merlion which is already marketed for the treatment of ear infections,s hows the same spectrum of activity as ciprofloxacin and cross-resistance to it. As aconsequence of its higher activity at lower pH values,itisdeveloped for UTI and kidney infections.…”